Antibody-drug conjugates: Intellectual property considerations · Antibody-drug conjugates: Intellectual property considerations Ulrich Storz* Michalski H€uttermann Patent Attorneys;

Antibody-drug conjugates: Intellectual property considerations

Ulrich Storz*Michalski H€uttermann Patent Attorneys; D€usseldorf, Germany

Antibody-drug conjugates are highlycomplex entities that combine an

antibody, a linker and a toxin. This com-plexity makes them demanding bothtechnically and from a regulatory pointof view, and difficult to deal with in theirpatent aspects. This article discusses dif-ferent issues of patent protection andfreedom to operate with regard to thispromising new class of drugs.

Introduction

Antibody-drug conjugates (ADCs) areone of the most promising classes of newdrugs, although the idea is not new.1

ADCs embody the oft-cited concept of“magic bullets,” which was described byPaul Ehrlich over 100 y ago. As of 2015,3 ADCs have been approved by theUS Food and Drug Administration(FDA), namely gemtuzumab ozogamacin(Mylotarg�), ado-trastuzumab emtansine(Kadcyla�) and brentuximab vedotin(Adcetris�). Their characteristics areshown in Table 1. More than 40 otherADCs are in clinical studies today.2

ADCs combine an antibody, a linkerand a toxin (often called “payload” or,more martial, “warhead”), and, for thatreason, they are technically demanding todevelop and pose challenges inmanufacturing.3 They can also raise regu-latory issues.4 because ADCs can be con-sidered prodrugs that release their activecompound–the toxin–at the site of action.

While their complexity has been calledan„invitation to innovation,”5 ADCs aredifficult to deal with in their intellectualproperty (IP) aspects. Both Freedom toOperate (FTO), as well as the protectionof ADCs and technologies to generatethem, are affected by the complexity ofthe molecules, and thus those who want

to develop and sell new ADCs or protectthe compounds and technologies fromwhich they are derived are faced with chal-lenges when making business decisions. Inaddition, the numerous players active inthis field have created a maze of third-party IP rights that is difficult to navigate.Further, because ADCs combine biotech-nology and organic chemistry, IP counselsworking in this area need a thorough tech-nical background in both disciplines.

This article discusses some of theseaspects in more detail, and discloses IPrights that stand exemplarily for a giventechnology or concept. It can, however,not replace a case-specific FTO analysis ornovelty search. Some of the IP rights dis-cussed herein may not have been grantedyet, or they may have already expired orbeen revoked. The latter, which aremarked with an asterisk in the respectivetables, may thus constitute free prior art,and, as such, provide a valuable source ofinformation for competitors.

Freedom to operateThe term “Freedom to Operate” refers

to a determination that the commerciali-zation of a product does not infringethird-party IP rights, in particular patents.Establishing FTO requires that all compo-nents of the respective technology, encom-passing methods as well as compoundsand intermediates, are analyzed withrespect to whether they are the subject ofvalid and enforceable third-party IP rights.

Because IP rights have a territorialeffect and a restricted lifetime only, anFTO analysis does not only focus on thetechnologies as such, but also considerswhere IP rights are in force and when theyexpire. In this context, the estimated timeto market of the product that is to be com-mercialized should be weighed against thelifetime of a given IP right. Further

Keywords: ADC, antibody-drug conju-gates, antibody, freedom to operate,immunotoxin, Kadcyla, patent

Abbreviations: FDA, Food and DrugAdministration; FTO, Freedom to Oper-ate; IP, Intellectual property; ADC, Anti-body-Drug Conjugates; EPO, EuropeanPatent Office; USPTO, United States Pat-ent And Trademark Office; CDR, Com-plementarity Determining Region; HC/LC, Heavy Chain/Light Chain; DAR,Drug-Antibody Ratio; IPR, Inter PartesReview; PTAB, Patent Trial and AppealBoard

*Correspondence to: Ulrich Storz; Email:[email protected]

Submitted: 05/28/2015

Revised: 08/03/2015

Accepted: 08/05/2015

http://dx.doi.org/10.1080/19420862.2015.1082019

www.tandfonline.com 989mAbs

mAbs 7:6, 989--1009; November/December 2015; © 2015 Taylor & Francis Group, LLCPERSPECTIVE

considerations should focus on potentialresearch exemptions as well as on ques-tions of exhaustion, or process patentsthat might extend their protection onproducts obtained therewith. These non-ADC specific regulations are subject tolarge variations between different jurisdic-tions, and thus are outside the scope ofthis article.

If, in the course of an FTO analysis, IPrights that are likely to be infringed by thecommercialization of a given product aredetected, one should consider whether ornot they are valid and enforceable. If not,respective countermeasures should be con-sidered, like invalidity opinions, opposi-tions, nullity actions, or post grant review/inter partes review.

As an alternative, in-licensing of therespective IP rights could be a solution.This approach is frequently used in caseswhere the patent protected technology isan enabling technology, or refers only to apart of the molecule, like a linker. Thesetechnologies have often been developed bytechnology companies who use out-licens-ing as their business model. Large bio-pharmaceutical companies are generallyless inclined to grant a license, in particu-lar on a compound-related patent, becausethey seek exclusivity rather than royalties.

For ADCs, an FTO analysis encom-passes all components, i.e., the antibody,the toxin and the linker. Numerous play-ers have already staked their claims, andmany patents and patent applications referto a combination of 2 of the components,very often a combination of a toxin and a

linker. The existing IP landscape thusappears more complicated than for nakedantibodies, with overlapping patent estatesassigned to different owners. Navigatingthis landscape can become a laboriouschallenge, and again requires a thoroughunderstanding of the technical back-ground, including biotechnology andorganic chemistry, and the filing strategiesused by competitors.

Further, inventors often believe that,once a patent has been granted on a giveninvention, FTO would be automaticallywarranted. This thinking relies on a mis-conception. The truth is that even if a pat-ent has been awarded on a structurallyimproved second-generation antibody, itcan still be the subject of earlier third-party patents protecting the starting anti-body, if these are still in force. In the fol-lowing sections, the methods andcompounds that are relevant in an ADCFTO analysis will be briefly addressed.

Active IP strategiesADCs do also offer new possibilities to

obtain patent protection. ADCs can, insome way, be considered as an advance-ment of conventional therapeutic antibod-ies, and, according to a general principle,each bit of advancement can be made sub-ject of a patent application.

According to a study performed atTufts University in 2007, the estimatedaverage costs of developing a new biologicwas 1.2 billion USD.6 This figure hasbeen adjusted upwards in 2014 to even2.6 billion USD.7 Further, development

times in biologics are slightly longer thanthose reported for small molecular drugs.8

Because of the higher complexity andthe higher regulatory burden, it can beassumed that, generally, these figures willbe even higher in ADCs. A meaningfulpatent strategy is thus indispensable toensure that these investments can be recu-perated over at least a given period oftime. ADC-related embodiments that canbecome subject of patent protection willalso be discussed in the following.

The antibody componentAn antibody as such can be subject of

third-party patents. This may encompass4 categories: 1) patents that protect anykind of antibody binding a particular tar-get, which at the filing date was novel(and specified by the applicant in a suffi-cient way as to enable skilled persons tomake an antibody thereagainst); 2) patentsthat protect all antibodies against a givenepitope of such target (if binding said epi-tope has unprecedented effect); 3) patentsthat protect all antibodies against a giventarget that have a particular functionality(e.g., minimum affinity, inhibition of agiven effect); or 4) patents that protect aspecific antibody (either defined by therespective expressor cell, or by a particularsequence, e.g., of the CDRs, the variabledomains or the HC/LC sequences).

It needs to be added, in this context,that new targets for ADC therapy are hardto find,9 thus making patents of categories1 and 2 less frequent nowadays. Further,it appears that the US Patent and

Table 1. Characteristics of the 3 ADCs approved to date by the US Food and Drug Administration

ADC nameAntibodytarget

Key IP rightUS/EP

Target alsoused in

conventionalmAb

therapy? LinkerLinker

cleavable? ToxinSite specificconjugation?

DrugAntibodyRatio

Gemtuzumabozogamicin**

CD33 US5773001/EP0689845B1*

no hydrazone yes calicheamicin no Only 50% of theantibody isloaded at all(avg 4 – 6)

Trastuzumabemtansine

HER-2/neu US8337856/EP2283867B1

yes SMCC (maleimide) no DM1 (maytansinoid) no 0–8 (avg 3,5)

Brentuximabvedotin

CD30 US7829531/EP2353611B1

no maleimidocaproylspacer, valine–citrulline linker,and PABC spacer

yes(cathepsin)

MMAE (auristatin) no 3–5

*expired; **product voluntarily withdrawn from the market in 2010.

990 Volume 7 Issue 6mAbs

Trademark Office (USPTO) and theEuropean Patent Office (EPO) havebecome more critical toward patents ofcategory 3 because a functional claim fea-ture is quite often considered to be a meredesideratum only, putting into questionthe true possession of the entire inventionby the applicant at the filing date, as wellas the inventive character involved.Regarding category 4, it seems that theEPO applies a higher standard than theUSPTO by requiring that the applicantdisclose some kind of surprising effect ofthe new sequence-wise specified antibodyover prior art antibodies addressing thesame target.10

As a general rule, all therapeutic anti-bodies on the market are, or were, pro-tected by such compound patents. Theuse of an approved antibody to generatean ADC is thus likely to fall under thescope of the respective naked antibodypatent, provided it is still in force. Thefact that the antibody is conjugated to atoxin does not per se change this situation.

In case the planned ADC comprises anexisting antibody that is already on themarket, or will enter the market, a thor-ough FTO analysis should be carried outin order to define when FTO can be

established, and in which markets. Thesame applies in cases where the target ofthe planned ADC is the subject of third-party patents. Patents of such type are onthe decline (simply because quite a fewtargets have already been described 10 yago or earlier), but still exist and providemeaningful patent protection. Table 2shows typical examples of different typesof naked antibody compound patents, asgranted by the EPO.

As shown above, some ADCapproaches use existing antibodies thathave already proven useful either in theclinic or in preclinical research, and mayhave a substantial global market. Forexample, trastuzumab, which as a soloproduct, generated global sales of 6.5 bnUSD in 2013.

As can be seen in Table 2, Claim 3 ofEP0590058 (which has expired June2012) protected Genentech’s anti-HER2antibody trastuzumab by its VL and VHsequence. ADCs comprising trastuzumab,such as Genentech’s ado-trastuzumabemtansine, would therefore fall underclaim 3 of EP0590058B1. Interestingly,claim 11 explicitly specified, as a preferredembodiment, an immunotoxin compris-ing trastuzumab plus a cytotoxin.

The use of an approved naked antibodyfor making an ADC has its merits. Forexample, it may appear useless to“reinvent the wheel,” i.e., to develop anew antibody when ones that bind rele-vant targets with high specificity and affin-ity are already on the market, and haveproven sufficiently safe and efficient to beapproved. However, not all therapeuticantibodies on the market are suitable asADCs.

For ADCs, internalization of the anti-body may be necessary, whereas, fornaked antibodies that evoke antibody-dependent cell-mediated cytotoxicity orcomplement-dependent cytotoxicity (e.g.,anti-CD20 rituximab), quick internaliza-tion would be counterproductive. Fur-ther, antibodies that bind cytokines (e.g.,anti-TNF adalimumab, anti-VEGF-Abevacizumab) instead of cell surface anti-gens are unlikely to be useful for ADCtherapy because they would not delivertheir toxin to a suitable target cell. Anideal ADC target should therefore: 1)reliably differentiate cancer cells fromhealthy cells; 2) occur in sufficientabundancy on the cell surface; 3) inter-nalize the bound ADC with sufficientspeed and efficacy.

Table 2. Examples of different types of naked antibody compound patents

Category Example IP right Assignee Target Claim language

Antibody claimed by its target ortarget epitope

EP1587837B1 Proscan RX PSMA An antigen comprising an immunogenic moiety orcarrier and an epitope of the extracellular region ofPSMA consisting of SEQ ID NO:8, wherein the N-terminal cysteine residue on SEQ ID NO:8 isoptional.

An isolated antibody or antigen binding fragmentthereof, which binds to the antigen wherein theantibody and/or antigen binding fragment thereofalso binds to PSMA.

Antibody claimed by functionalproperties

EP1347730B2 Seattle Genetics CD30 An antibody that immunospecifically binds CD30 andexerts a cytostatic or cytotoxic effect on aHodgkin’s disease cell line in the absence ofconjugation to a cytostatic or cytotoxic agent.

Antibody claimed by expressor cell EP0660721B1* Dana Farber CD22 A monoclonal antibody that: is produced by ahybridoma cell line selected from the groupconsisting of HB22–7 (ATCC No. HB 11347), HB22–22 (ATCC No. HB 11348) and HB22–23 (ATCC No.HB11349) [. . .]

Antibody claimed by sequence EP0590058B1* Genentech HER2 A humanized Antibody which comprises a VL domaincomprising the polypeptide sequence X and a VHdomain comprising the polypeptide sequence Y.

Antibody claimed by sequence EP1951757B1 Xencor CD30 An anti-CD30 antibody, comprising a variable heavychain sequence 1 and a variable light chainsequence 2

*expired; the symbol [. . .] indicates that claim language has been truncated.


Concerns have already been raised thatall acceptable targets meeting theserequirements have been discoveredalready, and that it is unlikely new oneswill be found. 11 Regardless, in the event anovel and suitable target for ADC therapyis found, it is definitely worth seeking pat-ent protection for antibodies against saidtarget on the basis of the classical catego-ries of antibody compound protection(see above). If the target is already knownbut has not yet been described as a targetfor ADC therapy, patent protection mayfocus on an ADC binding to said target.An example of the latter category is shownin Table 3.

In addition thereto, further develop-ments regarding the antibody concept assuch can be made the subject of patentprotection. This could involve, forexample, the use of new antibody for-mats or protein binders derived fromalternative scaffolds. Another approachis to modify antibodies in such way thatthey become active only at the tumorsite, even if they target an antigen that isexpressed both on healthy cells andtumor cells.12 This approach relies onspecific environmental conditions at thetumor site (e.g., abundance of proteases)to activate the antibody, thus avoidingdamage to healthy cells are bound. Insuch way, targets that are not druggabledue to insufficient discriminationbetween cancer cells and healthy cellscan be used. Still other approaches haveidentified targets that do not requireinternalization of the ADC. Accumula-tion of the ADC in the sub-endothelialextracellular matrix of tumors was foundefficient at very low side effects.13

Table 4 shows some of these approacheswhere the antibody concept has beenfurther developed, plus exemplary IPrights.

The linker technologyIn principle, a large variety of linker

technologies exists to bind small moleculesto proteins. A well-established technique isthe maleimide-based conjugation of thiol-comprising molecules to proteins. Thisapproach has often been used in first-gen-eration ADCs. Other linkers frequentlyused rely on hydrazone, disulfide or amidebonds.

Early attempts to improve linker tech-nology focused mainly on increasinglinker stability, to avoid cleavage thereofwhen the ADC is still in the bloodstream.These demands were met, e.g., by linkersdeveloped by Seattle Genetics or Immu-noGen. See Table 5 for some exemplaryIP rights. However, there was, and still is,further potential for innovation and,accordingly, new IP, in the field of ADClinker technology for various reasons,including insufficient linker stability,insufficient site specificity of the conjuga-tion or insufficient stoichiometry. Theseproblems affect the efficacy and safety ofan ADC and, as such, may pose challengesduring regulatory agency reviews. Newlinker technologies therefore strive to: 1)increase linker stability (and thus avoidcleavage thereof in the extracellular space);2) modulate cleavability after internaliza-tion (cleavage by plasma enzymes ormedium conditions, e.g., pH, allows thedrug to leak into neighboring cells; non-cleavable linkers release the toxin onlyafter degradation of the antibody); 3)increase site specificity of the conjugationsite to establish homogenicity of the ADCand avoid steric hindrance of the bindingdomains; or 4) increase stoichiometry(also called „drug-antibody ratio,” DAR)to yield sufficient efficacy of the ADC,e.g., by avoiding antibodies that carry notoxin, which would compete with theADC for target binding and thus affect

efficacy of the ADC. Table 6 shows somenew approaches related to ADC linkertechnology, and exemplary IP rights.

The toxinBefore the toxin component of a pro-

jected ADC is selected, considerationshould be given to whether the respectivetoxin is subject to third-party IP, and, ifso, where, and until when, and whether ornot it can be in-licensed. Today, 3 classesof toxins are typically used in ADCs,namely maytansinoids, auristatins, andcalcheamicins, but others are under inves-tigation. Table 7 shows some selected tox-ins and exemplary IP rights, some ofwhich refer to the combination of a toxinand a given linker or antibody.

Interestingly, of 47 ADC candidates inclinical studies as of 2014,14 16 candidatesuse maytansinoids, while 22 candidatesuse auristatins. In most cases, a license, ora purchase of the respective toxin, fromImmunoGen, or Seattle Genetics, respec-tively, would be necessary, because these 2companies are the major IP holdersregarding these toxins, or toxin-linkercombinations (see Table 7).

With respect to ado-trastuzumabemtansine, which carries ImmunoGen’smaytansinoid DM1, the original dealforged between Genentech and Immuno-Gen provided 2 mn USD upfront pay-ments, plus 44 mn USD in milestone androyalty payments.15 This is quite modestin view of the commercial power of ado-trastuzumab emtansine, which waslaunched in February 2013, achieved salesof 91 mn USD in the first half of 2013,and may achieve sales of 2.55 bn USD in2018 according to analysis by FiercePharma. It appears, however, that in morerecent deals, ImmunoGen has negotiatedmore favorable terms. A deal signed with

Table 3. Suitable patent category if target and antibody are known, but not in an ADC

Embodiment Target Example IP right Assignee Claim language

Target and antibody thereagainstare known, but not in an ADC

cKIt US20140271688 Novartis ADC of the formula Ab-(L-(D)n)n or a pharmaceuticallyacceptable salt thereof; wherein Ab is an antibodyor antigen binding fragment thereof thatspecifically binds to an epitope of human cKIT; L isa linker; D is a drug moiety; m is an integer from 1to 8; and n is an integer from 1 to 10.


Novartis in 2010 provided an upfrontpayment of 45 mn USD, and milestonepayments totaling »200 mn USD pertarget, plus royalties on the sales.ImmunoGen’s other deals include, amongothers, Eli Lilly (2011, 20 mn USDupfront and approximately 200 mn USDper target in milestones), Takeda (2015,440 mn USD upfront and milestones), orSanofi (2006, 32 mn USD upfront and

milestones per target),16 demonstratingthat there is substantial value even in justthe toxin technology used in ADCs.

The first experimental ADCs used cyto-toxic payloads that were already establishedin conventional chemotherapy, e.g., meth-otrexate,17 vinblastine.18 However, ADCshave a distinct advantage over conventionalchemotherapy because they can direct theirtoxic payload to the target tissue with high

specificity. For this reason, this approachopens the possibility to reduce non-specificside effects common to chemotherapy, thusbroadening the therapeutic window. Thisagain allows the use of toxic payloads thatotherwise would be too toxic for systemicadministration, or have a too short half-lifein the human plasma.

On the other hand, antibodies are rela-tively large molecules (the molecular

Table 4. Patents protecting new antibody concepts that can be used in ADCs

Technology Embodiment Example IP right Assignee Claim language

New antibody format Diabody EP2516462B1 Avipep An isolated protein comprising an immunoglobulinvariable region comprising:

(i) at least 2 cysteine residues positioned withinframework region (FR) 2, wherein if at least 2 of thecysteine residues in FR2 are not conjugated to acompound then a disulfide bond is capable of formingbetween the cysteine residues in FR2; and/or

(ii) at least 2 cysteine residues positioned withinframework region (FR) 3, wherein if at least 2 of thecysteine residues in FR3 are not conjugated to acompound then a disulfide bond is capable of formingbetween the cysteine residues in FR3.

ConditionallyactiveBiologics

Antibodies are activatedand/or inactivated at definedphysiological conditions.

US8709755 BioAtla A method of preparing a conditionally active antibody,the method comprising the steps of:

i. selecting a wild-type antibody against an antigen;ii. evolving the DNA which encodes the wild-type

antibody using one or more evolutionary techniquesto create mutant DNAs;

iii. expressing the mutant DNAs to obtain at least onemutant antibody;

iv. subjecting the at least one mutant antibody and thewild-type antibody to an assay under a normalphysiological condition selected from the groupconsisting of temperature, pH, osmotic pressure,osmolality, oxidation and electrolyte concentration,and to an assay under an aberrant condition selectedfrom the group consisting of temperature, pH, osmoticpressure, osmolality, oxidation and electrolyteconcentration; and

v. selecting the conditionally active antibody from the atleast one mutant antibody [. . .]

Cleavablemaskingpeptides

Masking peptides are released,e.g., by proteases secretedby the tumor

US20100189651 CytomX A modified antibody comprising: an antibody or antibodyfragment (AB), capable of specifically binding itstarget, coupled to a masking moiety (MM), wherein thecoupling of the MM reduces the ability of the AB tobind its target such that that the dissociation constant(Kd) of the AB when coupled to the MM toward thetarget is at least 100 times greater than the Kd of theAB when not coupled to the MM toward the target

Target which does notrequire toxininternalization

Extra domains A and B offibronectin

US20150030536 Philogen A method of treating lung cancer or lymphoma in anindividual, comprising administering to the individuala therapeutically effective amount of an antibody, orantigen-binding fragment thereof, which binds ExtraDomain-A (ED-A) of fibronectin comprising a VHdomain and a VL domain with given CDR sequencesand wherein the antibody is conjugated to a moleculethat has biocidal or cytotoxic activity or is conjugatedto a radioisotope.

the symbol [. . .] indicates that claim language has been truncated.


weight of an IgG is »150 KDa), comparedto which the toxin, which is commonly anorganic molecule, is small (molecularweight usually in the range of 0.3 to1 KDa). Therefore, the total amount oftoxin that can be administered with ADCtherapy is relatively small. Accordingly, anADC carrying 4 toxin molecules comprisesonly 0.8–2.67% w/w toxin. Further, it hasbeen reported that, despite the target speci-ficity an ADC has due to its antibody com-ponent, only 1.56% of the administereddose of the toxin will reach the intracellulartarget.19 This in turn means that a toxincandidate must show high potency to beuseful in ADC therapy.

As discussed already, 3 classes of toxinshave been typically used in ADCs, namelymaytansinoids, auristatins and calcheami-cins. Other classes are in clinical or preclinicaltrials,20 including pyrrolobenzodiazepinesand other benzodiazepine derivatives,duocarmycins, tubulysins, a-amanitin orbouganin protein toxin (see Table 7).

Most of these toxins are significantlymore potent than toxins used for conven-tional chemotherapy. In any case, the dis-covery of a new toxin (either a derivativefrom an existing class or a whole newclass) that can be used in ADCs can giverise to specific patent protection. Thesame applies for the transfer of an existingtoxin into the ADC context. Typical pat-ent categories that cover such types ofinnovations are shown in Table 8.

Second medical use patents and otherhigher generation patents

Second medical use claims strive toprotect the use of a given drug for a newindication discovered after the drug (andat least one medical indication) wasalready known. They usually specify thedrug and its new use in a language such as“antibody X for the treatment of diseaseY.”

If an ADC comprising a given anti-body is used for the treatment of a diseasethat is the subject of a third-party patentclaiming a second medical use of thatnaked antibody, it should be thoroughlychecked as to whether or not said use forthe ADC falls under the scope of said sec-ond medical use patent. The fact alonethat the antibody has been structurallymodified by conjugating a toxin theretodoes not automatically mean that it wouldno longer fall under the scope of such pat-ent, at least as long as the claim languagedoes not exclude such modification explic-itly. Similar logic applies to other highergeneration patents, like dosage patents orformulation patents, in which the claimsrefer to a naked antibody. However, itappears unlikely that an ADC using agiven naked antibody would use the samedosage or formulation.

Table 9 shows typical claim categoriesfor second medical use antibody patentsand other higher generation antibody pat-ents. With ADCs, the same rules exist as

with naked antibodies, and similar secondgeneration claim categories can hence begenerated. Table 10 shows some examplesof higher generation ADC patents.

Specific combination of antibodyand toxin

The specific combination of an anti-body and a toxin can be also patent eligi-ble. A given tumor cell type characterizedby a specific antigen can, for example, beparticularly susceptible to a given toxinconjugated to an antibody against said tar-get. In such case, patent claims providingthe broadest protection would merelyrecite the antibody target and the toxinclass.

If such a broad concept is already antic-ipated, or does not meet the non-obvious-ness/inventive step criterion, fallbackpositions for the antibody componentcould focus on a target epitope, a specificbinding behavior or a structurally definedantibody. For the toxin component, fall-back positions lie in a more restricted defi-nition of the specific toxin. Even thoughnarrow on paper, such restricted claimscan still provide meaningful patent protec-tion when backed by a respective market-ing authorization.

So far, the legal framework for ADCbiosimilar products is far from clear, andthe US and European Union regulatoryagencies have only recently begun evalua-tions of biosimilar antibodies. However,

Table 5. Early ADC linker technology patents

Technology Example IP right Assignee Claim language

Maleimidocaproyl-val-cit-PAB (combination withauristatins)

US7745394 Seattle Genetics 1. A method for treating cancer comprising administering to a patient in need thereofan effective amount of an antibody-drug conjugate compound having formula Ic:

Ab Aa-Ww-Yy-D)p Ic

wherein Ab is an antibody which binds to one or more tumor-associated antigensD is a drug moiety selected of Formula DE:

[ ]

Maytansinoids plus SMCClinker

US5208020* ImmunoGen A cytotoxic agent comprising one or more maytansinoids linked to a monoclonalantibody or fragment thereof via a disulfide bridge at the C-3,¡14,¡15, or¡20position of said maytansinoids and wherein said monoclonal antibody or fragmentthereof is selective for tumor cell antigens.

*expired; the symbol [. . .] indicates that claim language has been truncated.


Table

6.Pa

tentsprotectin

gne

wap

proa

ches

relatedto

ADClin

kertechn

olog

y

Tech

nolog

yEx

ample

IPright

Assignee

Claim

langua

ge

Non

-naturalam

inoacids

EP19

6863

5B1

Ambrx

Apo

lype

ptide,or

saltthereo

f,containing

atleasto

necompo

undselected

from

thegrou

pconsistin

gof:

whe

rein

each

R aisinde

pend

ently

selected

from

thegrou

pconsistin

gof

[...]

Cysteine-en

gine

ered

antib

odies(THIOMAB)

US200

7009

2940

Gen

entech

Acysteine

engine

ered

antib

odycomprisingon

eor

morefree

cysteine

aminoacidsha

ving

athiolreactivity

valuein

therang

eof

0.6to

1.0,

whe

rein

thecysteine

engine

ered

antib

odyisprep

ared

byaprocesscomprisingreplacingon

eor

moream

inoacid

residu

esof

apa

rent

antib

odyby

cysteine

.SM

AC(sortase-m

ediated

antib

odyconjug

ation)

with

N-terminalLPTX

Gtag/lin

ker

WO20

1414

0317

NBE

therap

euticsAmetho

dof

prod

ucingan

immun

oligan

d/pa

yloa

dconjug

ate,which

metho

den

compa

sses

conjug

atingapa

yloa

dto

anim

mun

oligan

dby

means

ofasequ

ence-spe

cifictran

spep

tidase,or

acatalytic

domainthereo

f.

SpaceLinkTechno

logy

EP13

7029

8B1

Syntarga

Acompo

undof

theform

ulaV-(W

) k-(X)

l-A-Z

whe

rein:

Visaspecifier

which

isremov

edby

anen

zyme,op

tiona

llyafterpriorbind

ingto

areceptor;

(W) k-(X)

l-Aisan

elon

gatedself-elim

inatingspacer

system

;Wan

dXareeach

a1,(4C2

n)electron

iccascad

espacer,being

the

sameor

differen

t;Aiseither

aspacer

grou

pof

form

ula(Y) m,w

herein

Yisa1,(4C2

n)electron

iccascad

espacer,ora

grou

pof

form

ulaUbe

ingacyclisationelim

inationspacer;

Zisatherap

eutic

ordiag

nosticmoiety;kan

dlare

inde

pend

ently

anintege

rfrom

0(in

clud

ed)to

5(in

clud

ed);m

isan

intege

rfrom

1(in

clud

ed)to

5(in

clud

ed);nisan

intege

rof0

(includ

ed)to10

(includ

ed),an

dkC1

>0.

Microbialtran

sglutaminase

(MTG

ase)

WO20

1420

2775

Inna

teAmetho

dforc

onjuga

tingahy

drop

hobic,high

molecular

weigh

torc

harged

orga

niccompo

undto

anan

tibod

y,comprising

thestep

sof:

a)prov

idingan

antib

odyor

antib

odyfrag

men

tcom

prisingan

acceptor

glutam

ineresidu

e;b)

reactin

gsaid

antib

odywith

alin

king

reag

entc

omprisingaprim

aryam

inean

damoietyof

interest(Z),whe

rein

(Z)isa

hydrop

hobiccompo

und,acharge

dorga

niccompo

undan

d/or

orga

niccompo

undha

ving

amolecular

weigh

tofa

tleast

500,70

0or

800g/mol,inthepresen

ceof

aTG

ase,un

derc

onditio

nssufficien

ttoob

tain

anan

tibod

ycomprisingan

acceptor

glutam

inelin

kedto

said

moietyof

interest(Z),viathelin

king

reag

ent[...]

SMART

agUS201

2018

3566

Redw

ood

Anisolated

alde

hyde

-tag

gedim

mun

oglobu

lin(Ig

)polyp

eptid

ecomprisingan

Igconstant

region

aminoacid

sequ

ence

comprisingan

aminoacid

sequ

ence

ofasulfatase

motif,

whe

rein

thesulfatase

motifispo

sitio

nedwith

inor

adjacent

asolven

t-accessibleloop

region

oftheIg

polype

ptideconstant

region

,and

whe

rein

thesulfatase

motifisno

tattheC-terminus

oftheIg

polype

ptidechain.

Tran

sglutaminaseC

“end

osom

eescaping

non

cleavable”

(EEN

C)linkers

USprov

isiona

l62/01

1,53

4,no

tpub

lishe

dyet

Dop

hen

Not

publishe

dyet

thesymbo

l[...]indicatesthat

claim

lang

uage

hasbe

entrun

cated.


Table

7.Pa

tentsprotectin

gselected

toxins

Tech

nolog

yEx

ample

IPright

Assignee

Claim

langua

ge

Auristatin

s(M

MAE,

MMAF)

US688

4869

Seattle

Gen

etics

Acompo

undof

theform

ula

andph

armaceu

ticallyacceptab

lesalts

andsolvates

thereof

whe

rein

[...]

Maytansinoids

plus

SMCClin

ker

US520

8020

*Im

mun

oGen

Acytotoxicag

entc

omprisingon

eor

moremaytansinoids

linkedto

amon

oclona

lantibod

yor

frag

men

tthe

reof

viaa

disulfide

bridge

attheC-3,¡

14,¡

15,or¡

20po

sitio

nof

said

maytansinoids

andwhe

rein

said

mon

oclona

lantibod

yor

frag

men

tthe

reof

isselectivefortum

orcellan

tigen

s.New

anthracyclin

deriv

atives

US890

0589

Gen

entech

Anan

tibod

y-drug

conjug

atecompo

undcomprisingan

antib

odycovalentlyattached

byalin

kerL

andan

optio

nalspa

cer

Zto

oneor

morean

thracyclinede

rivativedrug

moietiesD,the

compo

undha

ving

theform

ula(D-L-(Z)m)p-Abor

aph

armaceu

ticallyacceptab

lesaltthereo

f,whe

rein:A

bisan

antib

ody;

Disan

anthracyclinede

rivativeselected

from

thestructures

Aan

dB:

[...]

Caliche

amicins

US571

4586

American

Cyana

mid

Com

pany

Ametho

dforp

repa

ringmon

omericcaliche

amicin

deriv

ative/carrierc

onjuga

teswith

high

erdrug

load

ing/yieldan

dde

creasedag

greg

ationha

ving

theform

ula,

Pr(–X–

S–S–W)m

whe

rein:Prisaproteina

ceou

scarrier,Xisalin

kertha

tcom

prises

aprod

ucto

fany

reactiv

egrou

pthat

canreactw

itha

proteina

ceou

scarrier,W

isthecaliche

amicin

radicalformed

byremov

alof

thena

turally

occurringmethy

ltrisulfide

grou

p[...]

Duo

carm

ycins

EP25

6064

5A2

Syntarga

1.Acompo

undof

form

ula(III):

(Con

tinuedon

nextpa

ge)


whe

rein

[...]e

achZisinde

pend

ently

acompo

undof

form

ula(I),(II),(I’),or(IG):

[...]

Nov

eltaxane

sUS739

0898

Immun

oGen

Acompo

undrepresen

tedby

form

ula(I):

whe

rein

[...]

Pyrrolob

enzodiazep

ine

EP27

6604

8B1

ADCTh

erap

eutic

&Sp

iroge

nLimite

dAconjug

ateof

form

ulaCon

jB::

whe

reCBA

represen

tsacellbind

ingag

ent.

(Con

tinuedon

nextpa

ge)


Table

7.Pa

tentsprotectin

gselected

toxins

(Con

tinued)

Tech

nolog

yEx

ample

IPright

Assignee

Claim

langua

ge

a-aman

itin

EP24

3639

8B1

Heide

lbergPh

arma

Aconjug

atecomprisingatarget-binding

moietylin

kedviaalin

kerL

toan

amatoxin,w

herein

thelin

kerL

isconn

ectedto

theam

atoxin

via

(i)thegC-atom

ofam

atoxin

aminoacid

1,pa

rticularlyviaan

amidelin

kage

;(ii)anoxyg

enatom

boun

dto

thedC-atom

ofam

atoxin

aminoacid

3,pa

rticularlyviaan

esterlinkage

,anethe

rlinkage

orauretha

nelin

kage

;or

(iii)the60

C-atom

ofam

atoxin

aminoacid

4,pa

rticularlyviaan

oxyg

enatom

boun

dto

the60

C-atom

ofam

atoxin

amino

acid

4;in

each

case

whe

rein

thelin

kerL

isconn

ectedto

thetarget-binding

moietyviaaurea

moiety.

CC-106

5(duo

carm

ycin)

US547

5092

*

US558

5499

*Im

mun

oGen

Acytotoxicag

entc

omprisingacellbind

ingag

entlin

kedviaadisulfide

bond

toon

eor

morean

alog

sor

deriv

atives

ofa

cyclop

ropy

lben

zind

ole-containing

cytotoxicdrug

,whe

rein

said

cellbind

ingag

entisamon

oclona

lantibod

yor

anan

tigen

-binding

frag

men

tofa

mon

oclona

lantibod

yha

ving

atleasto

nebind

ingsite

thereo

f,an

dwhe

rein

priorto

linking

said

analog

sor

deriv

atives

tosaid

cellbind

ingag

entsaid

analog

sor

deriv

atives

areselected

from

thegrou

pconsistin

gof

analog

sor

deriv

atives

form

edfrom

anAsubu

nitof

theform

ulae

(A-3)o

r(A-4)and

aB-Csubu

nito

fthe

form

ulae

(F-3),(F-4),(F-5)o

r(F-6),saidB-Csubu

nith

avingaBmoietyshow

non

theleft-han

dside

oftheform

ulae

and

aCmoietyshow

non

therig

ht-han

dside

oftheform

ulae

andwhe

rein

said

Asubu

nitiscovalentlylin

kedto

said

B-C

subu

nitv

iaan

amidebo

ndfrom

thesecond

aryam

inogrou

pof

thepy

rrolemoietyof

theAsubu

nittotheC-2

carboxyl

grou

pof

theBmoietyof

theB-Csubu

nit,whe

rein

theform

ulae

(A-3)a

nd(A-4)are

asfollows

[...]w

herein

theform

ulae

(F-3)to(F-6)are

asfollows:

[...]

De-im

mun

ized

boug

anin

protein

toxin

US871

6234

Merck

Ametho

dof

inhibitin

gor

destroying

alymph

omacancer

cellcomprisingad

ministerin

gacytotoxinto

anan

imalha

ving

lymph

oma,whe

rein

said

cytotoxincomprises

atargetingmoietythat

bind

sto

thelymph

omacancer

cellan

dislin

ked

toamod

ified

boug

anin

protein,whe

rein

said

mod

ified

boug

anin

proteincomprises

AAsequ

ence

SEQID

NO:11,[...]

Tubu

lysins

US201

5141

646

Con

cortis

1.Acompo

undha

ving

thestructureof

Form

ulaI:

oraph

armaceu

ticallyacceptab

lesaltthereo

f,whe

rein:A

isatubu

linbind

ingmoiety;Bisafunctio

nalm

oiety;[...]

(Con

tinuedon

nextpa

ge)


Benzod

iazepine

deriv

atives

US876

5740

Immun

oGen

1.Acompo

undrepresen

tedby

thefollowingform

ula:

oraph

armaceu

ticallyacceptab

lesaltthereo

f,whe

rein:

thedo

ublelin

e–be

tweenNan

dCrepresen

tsasing

lebo

ndor

ado

ublebo

nd,[...]

Pyrrolob

enzodiazep

ine

US201

3028

919

Seattle

/Spiroge

nACon

juga

teha

ving

form

ula

L-(LU-D)p

oraph

armaceu

ticallyacceptab

lesaltor

solvatethereo

f;whe

rein

LisaLiga

ndun

it,LU

isaLink

erun

it,pis1to

20;and

DisaDrugun

itcomprisingaPB

Ddimer

having

thefollowingform

ulaII

whe

rein:R2is2’X[...]

Pyrrolob

enzodiazep

ines

US201

1025

6157

Spiro

gen

Aconjug

ateof

form

ula(A)

andsalts

andsolvates

thereo

f,whe

rein:the

dotted

lines

indicate

theop

tiona

lpresenceof

ado

ublebo

ndbe

twee

nC1

andC2or

C2an

dC3;

[...]

orthecompo

undisadimer

with

each

mon

omer

beingof

form

ula(A),or

with

onemon

omer

beingof

form

ula(A)and

theothe

rbeing

ofform

ula(B):

whe

rein

[...]

*exp

ired;thesymbo

l[...]indicatesthat

claim

lang

uage

hasbe

entrun

cated.


experience with regulations for genericsand biosimilars teaches that, once estab-lished, respective approval pathways donot allow any chemical modifications ofthe toxin or sequence modifications of theantibody. Therefore, although the scopeof such claims could theoretically bebypassed by even minor modification ofeither the toxin or the antibody, suchstrategy would necessitate an entirely newapproval, because the product would nolonger be a biosimilar. Table 11 showsexamples of patents claiming specific anti-body/toxin combinations.

Non-obviousness / inventive stepPatent claims relating to ADCs or their

components must pass the test on non-obviousness, as codified on 35 USC. x103, or its European counterpart, inven-tive step, as codified in Art. 56 of theEuropean Patent Convention. Both testsdecline patentability to an alleged inven-tion, even if it is novel, in case it was obvi-ous for a person of skill in the art in viewof existing prior art. In the US, differenttests have been applied in the past.

In the decision KSR v. Teleflex,21 theUS. Supreme Court set forth that the truetest of nonobviousness is the so called“Graham analysis,” thus denouncing a dif-ferent type of test that was used by thelower instance courts, which the SupremeCourt deemed too liberal. The SupremeCourt declared that the bar on patentsclaiming obvious subject matter shouldnot be confined within a test „too con-strained to serve its purpose.“ In the Gra-ham analysis, the courts examine thescope and content of the prior art, thelevel of ordinary skill in the art; the differ-ences between the claimed invention andthe prior art; and objective evidence ofnon-obviousness. Examples for the latterare, e.g., commercial success, long-felt butunsolved needs, and failure of others.

The EPO applies the so-called“problem solution approach.” In this test,the closest prior art is defined first. Sec-ond, the difference between the claimedinvention and the prior art is determined,and its technical effect is established.Accordingly, it is stipulated that it wouldbe the objective technical object of thealleged invention to obtain such effectstarted from the closest prior art. Eventu-ally, it is considered whether it was obvi-ous for the person of skill to solve thisobjective technical problem.

Despite all attempts to make the afore-mentioned tests as reproducible as possi-ble, large uncertainties still exist. Thepractical implementations differ not onlybetween the US and European Union orother jurisdictions, but also between dif-ferent technical disciplines, and evenbetween different examination divisions inthe same jurisdiction.

Table 12 gives an overview of theEuropean patents protecting gemtuzumabozogamicin, ado-trastuzumab emtansineand brentuximab vedotin (see alsoTable 1), and the reasons why the respec-tive examiner found the claimed subjectmatter inventive over the prior art. It canbe seen that in each case, the respectiveexaminer’s motif to allow the patent wasdifferent.

A look into the board of appeal deci-sions database of the EPO does not pro-vide better guidance either. In June 2015,only 2 decisions existed that relate to pat-entability issues of ADC patents, one ofwhich is referring to sufficiency of disclo-sure, while the other one refers to inven-tive step. Table 13 shows these 2decisions. Again, no true guidance can bederived from these decisions. Thus, unlikein naked antibody patent claims that spec-ify the antibody by a particular sequence,and where a clear guidance as to howinventive step is to be assessed exists,22 no

such guidance has so far been establishedwith respect to inventive step questions ofpatent claims for ADCs.

It needs to be recalled, in this context,that combining a particular toxin withsuperior potency and an antibody withexcellent target affinity does not necessar-ily yield a clinically effective ADC. Thebinding process, or the linker as such, canaffect either the toxin, or the antibody, orboth. Likewise, the toxin may not be ade-quate for the target bound by the anti-body. As can be seen in Table 12,Genentech has successfully used this lineof argumentation when defending theirpatent application EP2283867, protectingado-trastuzumab emtansine, over theirown prior art, which disclosed trastuzu-mab, plus generally mentioned the combi-nation thereof with maytansinoids.

For these reasons, the mere provisionof a functional ADC comprising a knowntoxin and antibody can already meet theinventive step criterion, at least in therecent past. However, with technical prog-ress, the likelihood that a prior art bench-mark exists already (e.g., an ADC using,for example, the same antibody, or at leastan antibody against the same target),increases. The patentee may in such casebe required to provide further arguments,or restrict the claim scope, to meet thenon-obviousness/inventive step criterion.

This criterion is thus a moving target,where, with technical progress of therespective discipline, requirements arechanged accordingly. Predictions of therequirements the offices will set withrespect to a given ADC patent applicationare thus educated guesses that take intoaccount the applicable state of the art, notonly with respect to the target, but alsowith respect to the toxin and the linkertechnology.

One objective evidence for inventivestep commonly accepted by EPO

Table 8. Claim categories for different types of toxin inventions

Subject matter Claim category Claim language

New class of toxin Compound protection Compound according to the general structural formula X, with R1 –Rx being [.]

Class is known, but specific toxin is novel Compound protection Compound of class X, having the following structural formula YClass or specific toxin is known, but

transfer to ADC is novel(i) Use/process protection or (ii) purpose

bound compound protection(i) Use of toxin x for the manufacture of an ADC(ii) Toxin x for use in an ADC for the treatment of cancer



examiners is if the novel embodiment hassurprising properties. In the ADC world,and in particular regarding specific anti-body-toxin combinations, this wouldmean that a specific characteristic of aclaimed ADC would be unprecedentedeven in view of the prior art benchmark.Such characteristic would not necessarilymean efficacy or potency. It could also bereduced side effects or, at least in the USand European Union, even non-clinicaladvantages, e.g., shelf life, ease ofmanufacture.

The problem of trade secretsThe term “trade secret” relates to a

product, process or know how thatprovides a commercial advantage to itsowner or creator, who, however, prefers tonot make it the subject of a patent

application. In some cases, creators orowners of such embodiments see it as aproblem that the content of a patentapplication is published after 18 months,while it is not yet clear at that timewhether a patent will be awarded on therespective subject matter or not. Further,if eventually granted, a patent expiresroughly after 20 years, after which thecontent of the patent becomes publicdomain. As a consequence, an inventionmay not be a subject of a patent applica-tion, but rather it may be kept a tradesecret. While this strategy does not workwith products that are to be sold (becauseputting them to the market without pat-ent protection makes such products publicdomain), it may have its merits withrespect to technologies, in particularmethods, that are practiced in-house, at

least in cases where a marketed productdoes not carry any traceable marks thatenable competitors to reverse-engineersaid technology.

A trade secret, however, is not an exclu-sive right. If the secret is disclosed, unin-tentionally, intentionally or even in badfaith, its content becomes public domainimmediately, and can be practiced bycompetitors. Therefore, in a strategy thatrelies on trade secrets, measures must betaken that ensure these secrets cannot bedisclosed, e.g., by former employees, norbe discovered by reverse-engineering. Incases when the owner of a trade secret col-laborates with third parties to whom saidtrade secret needs to be disclosed, non-dis-closure agreements should be signed. Incase such agreement is violated by thethird party, the latter will be liable for

Table 9. Claim categories for higher generation antibody patents

CategoryExample IPrights Assignee Target Claim language

2nd medical use EP1734996B1 University of California a vbeta 5 integrin Use of an antibody that specifically binds to a vbeta 5 integrin, wherein theantibody is a humanized form of the antibody produced by thehybridoma deposited as ATCC Deposit No. PTA-5817, for themanufacture of a medicament for treating pulmonary edema.

Dosage patent EP1210115B1* Genentech HER2 Use of the anti-ErbB2 antibody huMab 4D5 for treating a human patientdiagnosed with a breast cancer characterized by overexpression ofErbB2, said method comprising the steps of administering to the patientan initial dose of 8mg/kg of the anti-ErbB2 antibody; and administeringto the patient a plurality of subsequent doses of the antibody in anamount that is 6 mg/kg, wherein the doses are separated in time fromeach other by 3 weeks.

Formulation EP2459167B1 Roche HER2 A highly concentrated, stable pharmaceutical formulation of apharmaceutically active anti-HER2 antibody for subcutaneous injectioncomprising:

a. about 50 to 350 mg/ml anti-HER2 antibody;b. about 1 to 100 mM of a buffering agent providing a pH of 5.5 § 2.0;c. about 1 to 500 mM of a stabilizer or a mixture of 2 or more stabilizers;d. about 0.01 to 0.08 % of a nonionic surfactant; ande. more than 150 to about 160000 U/ml, about 20000 U/ml, or about

120000 U/ml, respectively of a hyaluronidase enzyme.

*EP Patent revoked in opposition, appeal pending. In UK finally revoked.

Table 10. Higher generation ADC patents

Category Example IP rights Assignee Target Claim language

2nd medical use US20110165155 Genentech HER2 A method for the treatment of metastatic or unresectable locallyadvanced HER2 positive cancer in a patient comprisingadministering a therapeutically effective amount of trastuzumab-MCC-DM1 wherein the patient has been previously treated with atleast 2 anti-HER2 agents.

Formulation WO2014143765 Abbvie EGFR A formulation comprising an anti-Epidermal Growth Factor Receptor(EGFR) antibody drug conjugate (ADC), a sugar, histidine, and asurfactant, wherein said formulation has a pH of about 5 - 7, andwherein said anti-EGFR ADC comprises an anti-EGFR antibody, orantigen-binding portion thereof, conjugated to an auristatin.


damages; however, the disclosure as suchinvolving the loss of the trade secret can-not be undone.

For ADCs, the supply chain can bevery long. While an innovator can beresponsible for a series of innovative tech-nologies covering the entire supply chainof an ADC (encompassing, antibodies,linker technology, toxins, methods ofproduction and so forth), reality showsthat, at least when commercializationstarts, different steps of the supply chain

are taken over by contract manufac-turers.23 In such an environment, wheredifferent steps are outsourced to differentpartners, a trade secret strategy bears par-ticular risks, which may result in the lossof a given trade secret and, accordingly,availability of the respective technologyto competitors. Therefore, ADC innova-tors should use trade secrets with utmostcare, and consider relying on patentapplications to protect their intellectualproperty.

Immunotoxins and radiolabelledantibodies

Although not specifically discussedherein, most of the principles set forthabove do also apply to immunotoxins andradiolabelled antibodies. Immunotoxinsare fusion proteins that consist of a target-ing protein, ideally an antibody, fused to atoxic protein. Immunotoxins offer advan-tages over ADCs in manufacture (becausethey can be produced by recombinantprotein expression in one step) as well as

Table 11. Examples of patents claiming specific antibody/toxin combinations

Category Example IP right Assignee Claim language

Combination of target and toxin class US8337856 ImmunoGen An immunoconjugate comprising an anti-ErbB2 antibody conjugatedto a maytansinoid, wherein the antibody is huMAb4D5–8

Combination of specific antibody and toxin US8153768 Wyeth HoldingsCorporation

A composition comprising a drug conjugate, wherein said drugconjugate comprises calicheamicin derivatives and an anti-CD22antibody and has the formula:

[b]wherein the antibody comprises SEQ ID NO. [. . .]


Table 12. European patents protecting gemtuzumab ozogamicin, ado-trastuzumab emtansine and brentuximab vedotin

EP Patent Claimed subject matter Closest prior art Why inventive?

EP0689845B1* ADC with calicheamicin andhydrazine linker

EP0392384 discloses Calicheamicinsuccinimidyl derivativesconjugated to an antibody

Examiner accepted that “nothing in the prior art suggeststhat the use of the current linker system to bindcalicheamicin to an antibody would yield conjugateshaving high immunoaffinity to the target, low toxicityand high antitumour activity.” (EP office action of May 11,2001)

EP2283867B1 Trastuzumab maytansinoidconjugate for treatment ofcancer over-expressingErbB2

WO0069460 discloses trastuzumab,plus generally mentionscombination therof withmaytansine

Examiner accepted applicant’s arguments of Nov 18, 2013,that (i) the specific selection of trastuzumab andmaytansine would be novel over WO’460. In support ofinventive step, applicant argued (ii) against Chari et al(1992), which discloses a murine anti-cancer ADCcomprising a maytansinoid and an anti ErbB2 antibodyas not being the closest prior art, and (ii) that it wassurprising that trastuzumab retained its cytostatic activityin an ADC, and would not be degraded to a meretargeting device, thus leading to an ADC where theantibody and the toxin act in concert. Applicant had alsoargued that at the priority date, there was uncertaintyregarding the therapeutic potential ofimmunoconjugates.

EP2353611B1 ADC with Pentapeptide linkerplus auristatin

WO02088172 disclosespentapeptide linkers, and ADCsusing them, but not auristatin

WO0208817 was the only prior art document, but althoughpre-filed, published after the priority date, and did thusnot affect inventive step

*expired


to site specificity and stoichiometry of theconjugation. Disadvantages may lie in anincreased immunogenicity. So far onlyone immunotoxin has received approvalin the US, namely denileukin diftitox(Ontak�), which consists of an interleu-kin-2 protein fused to a diphtheria toxin.

Radiolabelled antibodies are antibodiesthat carry a radioactive isotope. Theseconjugates do not have to be internalizedinto the cells to become effective, and canthus also be used to attack cellular targetsthat do not involve internalization, justlike the CD20 receptor. Two radiolabelledantibodies have been approved, Gen-entech’s 90Y ibritumomab tiuxetan(Zevalin�; Key IP right: EP1112084B1)and 131I tositumomab (Bexxar�; Key IPright: US6090365; marketing discontin-ued in 2014), which both include an anti-CD20 antibody component. Both havebeen the subject of litigation betweenGenentech and GlaxoSmithKline.24

Case study 1Because of their commercial potential,

ADC patents will inevitably become thesubject of IP litigation. One very recentdispute is evolving between Phigenix,based in Atlanta, Georgia, and Genentechof South San Francisco. Phigenix, who ontheir website claim that they “will leveragelicensed patented technology to establish astrong first-mover advantage in Personal-ized Medicine and forge a lasting leader-ship position in the rapidly evolving

cancer diagnostic and therapeuticsindustry,” has in 2014 filed requests forinter partes review (IPR) against Gen-entech’s US Patent 7575748 (IPR2014–00842) and ImmunoGen’s US patent8337856 (IPR2014–00676), which bothprotect Genentech’s ADC ado-trastuzu-mab emtansine. Further, Phigenix suedGenentech on Jan 31, 2014 for patentinfringement of their own US patent8080534 in the Georgia Northern DistrictCourt (1:14-cv-00287). Table 14 showsthe respective patents and selected claimlanguage. As discussed above, Genentechhas acquired a license from ImmunoGenfor use of the SMCC linker and the DM1toxin conjugated to trastuzumab. A conju-gate of said toxin-linker combination withan antibody was protected, among others,by ImmunoGen’s patent US5208020(now expired; see Table 5).

On December 9, 2014, the PatentTrial and Appeal Board (PTAB) of theUSPTO denied institution of IPR2014–00842 against US7575748, on thegrounds that Phigenix did not establish areasonable likelihood of prevailing withrespect to any challenged claim. Phigenix’attacks were based on alleged obviousnessin view of the trastuzumab (Herceptin�)1998 label and several prior art docu-ments. According to the Board, whichapplied the “broadest reasonable construc-tion in light of the specification of the pat-ent,” Phigenix failed to explain adequatelyhow, nor provided sufficient evidence

indicating that, the teaching in the trastu-zumab label that certain patients failed torespond to the product would have moti-vated an ordinary artisan to treat suchpatients using a trastuzumab (huMab4D5–8) conjugate.

In contrast thereto, IPR2014–00676against US8337856 was instituted onOctober 29, 2014. The PTAB found thatPhigenix has demonstrated that there is areasonable likelihood that it would prevailon the ground that claims 1–8 of the pat-ent would have been obvious over some ofthe prior art documents in view of thetrastuzumab label. This, however, is not afinal determination on the patentability ofthe challenged claims. IPR proceedingswere thus instituted. The case is ongoingas of mid-2015.

Regarding the litigation at the GeorgiaNorthern District Court, Phigenixasserted that Genentech would infringetheir patent US8080534 via certain acts,“directly and/or indirectly, of making,using, selling, or offering for sale the drugado-trastuzumab emtansine under thetrade name Kadcyla�, and inducinghealthcare professionals to prescribe andadminister Kadcyla�,” among others bydistribution of the respective prescribinginformation.

The infringement contentions wereserved to Genentech’s attorneys in Sep-tember 2014, but are so far not public yet.As of mid-2015, Phigenix has not publiclydisclosed which part of ado-trastuzumab

Table 13. Abstract of the 2 EPO Appeal decisions that relate to ADC patents

Decision Date Patent/ application Claimed subject matter Outcome

T 0619/01 August 2004 EP0634938A1* conjugate of SMPT linked-humanizedM195 antibody and 2-iminothiolanemodified gelonin or recombinantgelonin for the treatment of leukemia

Claims found unallowable for insufficient disclosure,because the term “term “recombinant gelonin” wasnot properly defined. The only vague definition(JM105 E. coli expressing optimized gelonin”)would leave the burden of finding out how toarrive at recombinant gelonin entirely upon theskilled reader.

T 1014/01 Nov 2003 EP0439095B1** Antibody-based fusion proteincomprising an Ig portion capable ofdirecting the fusion protein to a tumor,an IL2 molecule capable of promotinglymphocyte proliferation, and amodified IgG1 hinge region with the 2Cys residues replaced by Pro andSerine to permit greater flexibility inthe fused molecule.

Claim 1 (3rd request) was found inventive becauseprior art suggested that the hinge feature wouldavoid the reactive side groups in the AA sequence,not for increasing the flexibility. Further, prior artwould contains no pointer to replace Cys with Pro,while prejudice against the use of Pro (“helix-killer”)would exist.2nd request, which recited, as an alternative, also anatural hinge region, was not deemed inventive.

*rejected; **expired


emtansine they believe to inhibit PAX2expression or PAX2 activity and/or expressDEFB1, as set forth in claim 1 ofPhigenix’s patent. However, dependentclaim 15 stipulates that the therapy canalso comprise administration of an anti-Her-2 agent. This suggests that Phigenixconsiders the DM1 toxin as the part ofado-trastuzumab emtansine that inhibitsPAX2 expression or PAX2 activity and/orexpresses DEFB1, as set forth in claim 1,while the trastuzumab part would bedefined in said dependent claim 15.

Furthermore, claim 19 claims adminis-tering the composition to a patient afterdetermining the PAX2-DEFB1 expressionratio and the ER/PR status in a breast can-cer tissue isolated from the patient. How-ever, the prescribing information,25 ofado-trastuzumab emtansine does not men-tion either PAX2 or DEFB1. Therefore, itremains unclear so far what exactly theinfringement contentions refer to. Uponmotion of Genentech, the infringementaction was transferred to the NorthernDistrict of California Court on March 17,

2015 (3:2015cv01238), where it is stillpending.

This case impressively demonstrateshow even originators of a naked antibodycan run into patent litigation when mar-keting an ADC, even if said ADC com-prises their established antibody, and evenif the respective toxin and linker technol-ogy have been in-licensed. Further, thiscase shows that even having obtained alege artis FTO opinion – an exercise Gen-entech has undoubtedly gone throughbefore marketing ado-trastuzumab

Table 14. Patents that play a role in the Phigenix-Genentech dispute

Novel embodiment Assignee Case No Claim language

US7575748 Genentech IPR2014–00842 1. A method for the treatment of a tumor in a mammal, comprising the steps of (i)identifying said tumor as being characterized by overexpression of an ErbB2 receptorand as being a tumor that does not respond, or responds poorly, to treatment with ananti-ErbB antibody, and (ii) intravenously administering to the mammal atherapeutically effective amount of a conjugate of a humanized antibody huMab 4D5–8covalently linked via a thioether linking group with a maytansinoid DM1 having thestructure

at a dose of between about 0.2 mg/kg and about 10 mg/kg (antibody-maytansinoidconjugate weight/body weight) and at a frequency of dosing selected from the groupof dosing frequencies consisting of bolus, less than about 1 time per week, one time perweek, 2 times per week, more than 2 times per week, and continuous infusion,whereby said tumor characterized by overexpression of an ErbB2 receptor and thatdoes not respond, or responds poorly, to treatment with an anti-ErbB antibody, istreated.

US8337856 ImmunoGen IPR2014–00676 1. An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid,wherein the antibody is huMAb4D5–8

US8080534 Phigenix 1:14-cv-00287 1. A method for treating a breast condition in a subject, comprising administering to abreast tissue of the subject, a composition that(1) inhibits PAX2 expression or PAX2 activity,(2) expresses DEFB1 or(3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1.15. The method of claim 1, further comprising the step of: administering to the subjectan effective amount of an anti-HER-2 agent.16. The method of claim 15, wherein the anti-HER-2 agent is trastuzumab.19. A method for treating a breast condition in a subject, comprising:(a) determining the PAX2-to-DEFB1 expression ratio in a diseased breast tissue fromsaid subject;(b) determining the ER/PR status of said diseased breast tissue from said subject; and(c) based on the results of (a) and (b), administering to a breast tissue of said subject, afirst composition that (1) inhibits PAX2 expression or PAX2 activity, (2) expresses DEFB1or (3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1.


emtansine – does not provide a guaranteeagainst IP attacks from unforeseen cor-ners. This again demonstrates the com-plexity of the IP landscape in the ADCfield, and the residual risk players mustdeal with even with a proper FTO opinionin their hands.

Phigenix also filed an oppositionagainst ImmunoGen’s EP counterpart ofUS patent 8337856, EP2283867 (seeTables 1 and 12) on February 19, 2015.In the opposition, Phigenix alleges thatthe patent claims would lack novelty overWO0069460, and lack inventive stepover, among others, a journal article auth-ored by Chari et al.,26 and the trastuzu-mab label, in combination with otherdocuments disclosing maytansinoid tox-ins. While Phigenix thus largely relies onprior art that has already been consideredby the office (see Table 12), their mainline of argumentation is that the selectionof trastuzumab and a maytansinoid wouldnot be a specific selection that would pro-vide novelty over WO0069460. Further,they argue that Chari et al. would indeedbe the closest prior art, as it relates to afunctional anti-cancer ADC comprising amaytansinoid and a murine anti-ErbB2antibody, thus rebutting Genentech’sarguments according to which it was sur-prising that trastuzumab retained its cyto-static activity in an ADC, and would notbe degraded to a mere targeting device.

A first decision in this case cannot beexpected prior to mid-2016. Interestingly,on February 2015, Genentech receivedthe allowance for another EP applicationof the same family, EP2283866, with analmost identical claim scope. The opposi-tion term of this patent will be open untilNovember 2015.

Case study 2HER2 seems to be an attractive target

for ADC therapy, not only because it hasproven safe and efficacious in antibodytherapy, but also because it meets theother requirements set forth above,including rapid internalization.27 Unsur-prisingly, Genentech is not the only com-pany that has an anti-HER2 ADC intheir portfolio. In some way, ado-trastu-zumab emtansine can be considered afirst-generation ADC, while second-

generation anti-HER2 ADCs are alreadyunder development.

Based in Nijmegen, The Netherlands,Synthon has developed SYD985, whichcomprises trastuzumab conjugated to acleavable linker and duocarmycin pay-load. According to Synthon, SYD985 isalso active against tumors that exhibitlow expression of HER2, and does thusallow extension of the target populationof cancer patients who may respond tothis treatment to include FISH (fluores-cence in situ hybridization)-negative/immunohistochemistry (IHC)-HER2 1Cand 2C patients.28 According to theFDA label, ado-trastuzumab emtansineis, however, only indicated for the treat-ment of patients with HER2-positivebreast cancer in which the tumors showHER2 overexpression defined as 3CIHC. While trastuzumab is beginning tocome off patent (EP0590058 has expiredJune 15, 2012), the linker technologyand the duocarmycin used in SYD985are being pursued in pending applicationEP2560645 (see Table 12), assigned toSyntarga, which is a subsidiary of Syn-thon. Although SYD985 addresses a simi-lar market as ado-trastuzumab emtansine,and clinical trials are currently underway,29 it has, so far, not been subject of apatent litigation by third parties. Itappears that SYD985 would at least notfall under the scope of US8337856 pro-tecting ado-trastuzumab emtansine (seeTable 15) because SYD985 does notcomprise a maytansinoid.

The same circumstances apply to theanti-HER2 ADC ARX788 developed byAmbrx. ARX788 comprises an anti-HER2antibody coupled site specifically to a toxincalled Amberstatin (AS269) by means ofAmbrx’ technology using non-naturalamino acids (EP1968635B1, see Table 6).Like Synthon, Ambrx claims that ARX788serves a broader spectrum of HER2C can-cer patients than ado-trastuzumab emtan-sine. Similarly, it appears that ARX788has so far not been the subject of a patentlitigation by third parties. ARX788 is cov-ered by Ambrx’s international patentapplication WO2013192360. The linker,toxin and antibody are not chemicallyspecified, but according to a report pub-lished in 2012,30 it appears that the anti-body could be a modified trastuzumab

that carries a p-acetylphenylalanine (pAc-Phe) residue instead of a naturally occur-ring amino acid reside, to which analkoxy-amine derivatized auristatin F(MMAF) is conjugated by oxime ligation.

Another anti-HER2-toxin construct inclinical development is MM-302 devel-oped by Merrimack Pharmaceuticals Inc.MM-302 is not a conjugate in strictusensu because it consists of a liposome75–110 nm in diameter that encapsulatesdoxorubicin. The lipid membrane is com-posed of phosphatidylcholine, cholesterol,and PEGylated phosphatidylethanolamine(1 PEG molecule for 200 phospholipidmolecules), wherein one PEG moleculefor each 1780 phospholipid moleculesbears at its end an anti-HER2 scFv anti-body fragment called F5.31

Exact targeting is critical in this ADCbecause cardiomyocytes, which are affectedby the highly cardiotoxic doxorubicin,must be avoided. The fact that doxorubicnis encapsulated by liposomes further pro-tects the cardiomyocytes. As with SYD985and ARX788, it appears that MM-302,which is covered by international patentapplication WO2012078695, has so farnot been subject of a patent litigation bythird parties.

Dophen Biomed of Sacramento, USA,has recently presented results32 on an anti-HER2 ADC consisting of trastuzumaband MMAE, conjugated to one anotherby Dophen’s transglutaminase usingDophen’s endosome escaping non-cleavable” (EENC) linkers (see Table 6).The company claims that this ADC has100% stability and higher potency than acomparable ADC with a cleavable linker.Further, Dophen uses this technology togenerate anti-HER2 ADC comprisingtrastuzumab and 2 different toxins ofundisclosed nature. Quite apparently, atleast one of these toxins is a tubulysinbecause of a collaboration with Austriantubulysin specialist Tubepharma.33 It hasbeen reported that such a hybrid ADC hasbetter potency than the respective homo-geneous ADCs of the same toxins, andalso better potency than a 1:1 mixture ofthe 2 homogeneous ADCs. No patentinformation is available for Dophen’stechnologies.

NBE Therapeutics of Basel, Switzer-land, has created different anti-HER2


Table

15.D

etailsof

differen

tan

ti-HER

2ADCsin

developm

ent

ADCnam

eAntibod

yLinke

rTo

xin

Key

IPright

Com

pan

yStatus

Claim

langua

ge

Trastuzumab

emtansineTrastuzumab

SMCC

DM1

US833

7856

Gen

entech

App

rovedin

USan

dEU

Anim

mun

ocon

juga

tecomprisingan

anti-ErbB

2an

tibod

yconjug

ated

toamaytansinoid,

whe

rein

thean

tibod

yishu

MAb4

D5–

8.MM-302

scFv

anti-HER

2PE

G-DSP

ELipo

some-

encapsulated

doxorubicin

US201

4023

698

Merrim

ack

Phase2/3

Ametho

dof

treatin

gahu

man

cancer

patie

ntby

administrationof

anthracycline-com

prisingan

ti-HER

2im

mun

oliposom

es,the

metho

dcomprisingde

term

iningafirstd

osag

e,such

ado

sage

indicatin

gado

semag

nitude

andfreq

uencyof

dosing

,for

apa

tient

diag

nosedwith

acancer

characterized

byexpression

ofHER

2receptor,the

firstd

osag

ebe

ingfora

liposom

alan

thracycline

chem

othe

rape

uticag

enttha

tdoe

sno

tcom

prisean

immun

oliposom

e,which

dosage

isde

term

ined

toprov

ideto

the

patie

ntasafe

andeffectiveam

ount

ofthelip

osom

alform

ulation,

andad

ministerin

gan

thracycline-comprisingan

ti-HER

2im

mun

oliposom

es,a

plurality

ofwhich

immun

oliposom

esiseach

bearingaplurality

ofan

ti-HER

2an

tibod

ymolecules

onits

surface

andeach

containing

thean

thracyclinechem

othe

rape

uticag

ent,

whe

rein

thean

thracycline-comprisingan

ti-HER

2im

mun

oliposom

esaread

ministeredto

thepa

tient

atthefirst

dosage

.

SYD98

5Trastuzumab

SpaceLink

Duo

carm

ycin

EP25

6064

5A2

Syntarga

Phase1

Acompo

undof

form

ula(III):

oraph

armaceu

ticallyacceptab

lesalt,hy

drate,or

solvatethereo

f,whe

rein

[...]

(Con

tinuedon

nextpa

ge)


ARX

788

Und

isclosed

Und

isclosed

Ambe

rstatin

AS269

US201

5141

624

AmbrX

Preclin

ical*

whe

rein

[...]

Not

available

Trastuzumab

Tran

sglutaminase

CEENClin

ker

MMAE,hy

brid

ADCswith

differen

ttoxins

Not

available

Dop

hen

R&D

Not

available

Not

available

Trastuzumab

SMACwith

N-terminal

LPTX

Gtag/lin

ker

(i)DM1(m

ertansine),

(ii)m

aytansine,

(iii)MMAE/MMAF

(iv)a

-aman

itin

(v)u

ndisclosed

newtoxin,

respectiv

ely

(i)–(iv)

WO20

1414

0317

(v)n

otdisclosed

NBETh

erap

euticsR&

D1.Ametho

dof

prod

ucingan

immun

oligan

d/pa

yloa

dconjug

ate,

which

metho

den

compa

sses

conjug

atingapa

yloa

dto

anim

mun

oligan

dby

means

ofasequ

ence-spe

cifictran

spep

tidase,

oracatalytic

domainthereo

f.6.Th

emetho

daccordingto

anyof

theaforem

entio

nedclaims,

whe

rein

thesequ

ence-spe

cifictran

spep

eptid

aseisat

leasto

neselected

from

thegrou

pconsistin

gof

�asortaseen

zyme,or

oneor

morefrag

men

tsor

deriv

atives

thereo

f�a

split-in

tein,oro

neor

morefrag

men

tsor

deriv

atives

thereo

fNot

available

Trastuzumab

N-Hyd

roxysuccinim

ide

ester

Tubu

lysin

Not

available

VUMC

Amsterda

mR&

DNot

available

*Pha

se1stud

y(NCT025

1223

7)sche

duledto

startin

Septem

ber2

015;thesymbo

l[...]indicatesthat

claim

lang

uage

hasbe

entrun

cated.


ADCs with trastuzumab using their sor-tase-mediated antibody conjugation tech-nology (SMAC) with N-terminal LPTXGtag/linker (see Table 6, WO2014140317)to couple trastuzumab to DM1 (mertan-sine), maytansine, MMAE, MMAF anda-amanitin, and thus create ADCs withsite-specifically conjugated toxins ofhomogeneous DAR. The first 2 have beenreported to be equally potent as ado-tras-tuzumab emtansine. Another ADC com-prises an undisclosed new toxin, whichhas demonstrated significantly betterpotency in cells expressing only lowamounts of HER2 than ado-trastuzumabemtansine.34

Still another anti-HER2 ADC has beendeveloped by researchers of the VU Uni-versity Medical Center Amsterdam, whoused a moderately toxic tubulysin analog(TUB-OMOM). Tubulysins have a nar-row therapeutic window and are thusinteresting for ADC use. For this purpose,tubulysin-NHS-esters were coupled totrastuzumab, while for control purposes,131I-tubulysin and 89Zr-trastuzumab wereused. The conjugation reaction was 45–55% efficient, resulting in ADCs with96–98% radiochemical purity and anaverage DAR of between 2 and 4. Theresearchers report a potency comparableto that of ado-trastuzumab emtansine,while the availability of synthetic tubuly-sins that are more potent than TUB-OMOM offers additional options tomake more potent ADCs.35 No patentinformation is available for this approach.Table 15 shows some details of the anti-HER2 ADCs discussed above.

Summary

Regarding IP aspects, ADCs posesevere challenges, but also tremendouspossibilities. ADCs comprise a field oftheir own, in which only part of the rulescan be translated from antibody IP. Fur-ther, because many players are active inthis field, the third-party IP situation iscomplicated, with many overlapping pat-ent estates. A meaningful IP strategy forprotecting ADC inventions and establish-ing FTO requires specific expertise in thischallenging IP discipline, as well as a

thorough technical understanding of bothbiotechnology and organic chemistry.

Disclosure of Potential Conflicts of Interest

The author is involved in the prosecu-tion of some of the patent applicationsmentioned herein.

The information provided hereinreflect the personal views and considera-tions of the author. They do not representlegal counsel and should not be attributedto Michalski ¢ H€uttermann and PartnerPatent Attorneys or to any of its clients.Patent numbers and patent lifetimes havebeen verified with utmost care, but no lia-bility is taken for their correctness.

Supplemental Material

Supplemental data for this article canbe accessed on the publisher’s website.

References

1. Beck A, Reichert JM. Antibody-drug conjugates: pres-ent and future. MAbs 2014; 6(1):15-17;PMID:24423577

2. Rostami S, Qazi I, Sikorski R. The Clinical Landscapeof Antibody-drug Conjugates. ADC Review 2014;August 1, 2014.

3. Rohrer T. Consideration for the safe and effectivemanufacturing of antibody drug conjugates. ChemistryToday 2012; 30(5):76-79.

4. Wu WJ. Regulatory Perspective on Challenges in ADCDevelopment (Keynote presentation) PepTalk 2015;January 19–23; 2015, San Diego, CA.

5. Lash A. Antibody-drug conjugates: the next generationof moving parts. START-UP 2001; 27 Dec 2011.

6. DiMasi JA, Grabowski HG. The cost of biopharmaceu-tical R&D: is biotech different? Manag Decis Econ2007; 28:469-479.

7. Mullard A. New drugs cost US$2.6 billion to develop.Nature Reviews Drug Discovery 2014; 13(12):877-877

8. Grabowski H, Cockburn I, Long G. The market for fol-low-on biologics: how will it evolve? Health Affairs(Project Hope) 2006; 25(5):1291-301;PMID:16966725


10. Stewart M, Kent L, Smith A, Bassinder E. The specialinventive step standard for antibodies. epi information2011; 2/2011:72-76.

11. Bander NH. Antibody-drug conjugate target selection:critical factors. Methods Mol Biol 2013; 1045:29-40;PMID:23913139

12. Erster O, Thomas JM, Hamzah J, Jabaiah AM, GetzJA, Schoep TD, Daugherty PS. Site-specific targetingof antibody activity in vivo mediated by disease-associ-ated proteases. J Control Release 2012; 161(3):804-12

13. List T, Neri D. Biodistribution studies with tumor-tar-geting bispecific antibodies reveal selective accumula-tion at the tumor site. mAbs 2012; 4(6):775-83;PMID:23032949

14. Rostami S, Qazi I, Sikorski R. The clinical landscape ofantibody-drug conjugates. ADCReview 2014; August1, 2014.


16. ImmunoGen press releases of October 11, 2013(http://investor.immunogen.com/releasedetail.cfm?ReleaseIDD796395); December 20, 2011 (http://investor.immunogen.com/releasedetail.cfm?ReleaseIDD634459); March 23, 2015 (http://investor.immunogen.com/releasedetail.cfm?ReleaseIDD902766) andDecember26, 2006 (http://www.biospace.com/News/immunogen-inc-announces-that-sanofi-aventis-has/41104).

17. Endo N, Takeda Y, Umemoto N, Kishida K, WatanabeK, Saito M, Hara T. Nature of linkage and mode ofaction of methotrexate conjugated with antitumor anti-bodies: implications for future preparation of conju-gates. Cancer Res 1988; 48(12):3330-5; Retrieved fromhttp://cancerres.aacrjournals.org/content/48/12/3330.short; PMID:3259466

18. Starling JJ, Maciak RS, Hinson NA, Nichols CL, BriggsSL, Laguzza BC. In vivo efficacy of monoclonal anti-body-drug conjugates of three different subisotypeswhich bind the human tumor-associated antigendefined by the KS1/4 monoclonal antibody. CancerImmunol Immunother 1989; 28(3):171-8; Retrievedfrom http://www.ncbi.nlm.nih.gov/pubmed/2784353;PMID:2784353

19. Teicher BA, Chari RVJ. Antibody conjugate therapeu-tics: challenges and potential. Clin Cancer Res 2011;17(20):6389-97; PMID:22003066; http://dx.doi.org/10.1158/1078-0432.CCR-11-1417

20. Rostami S, Qazi I, Sikorski R. The Clinical Landscapeof Antibody-drug Conjugates. ADCReview 2014August 1; 2014.

21. Decision KSR Int’l Co. v. Teleflex, Inc., 550 US 398,US Supreme Court 2007.

22. Stewart M, Kent L, Smith A, Bassinder E. The specialinventive step standard for antibodies. epi information2011; 2/2011; 72-76.

23. Wooge C, Swamy J. Next-Gen ADCs: collaborating toimprove supply chains for development and technologytransfer with novel technology platforms. ContractPharma 2014; Nov/Dec 2014; 16(9):50.

24. Storz U. Rituximab: how approval history is reflectedby a corresponding patent filing strategy. MAbs 2014;6(4):820-37; PMID:24866199; http://dx.doi.org/10.4161/mabs.29105

25. Prescribing information for Kadcyla� (Ado-trastuzu-mab emtasine); http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf

26. Chari RV, Martell BA, Gross JL, Cook SB, Shah SA,Bl€attler WA, Goldmacher VS. Immunoconjugates con-taining novel maytansinoids: promising anticancerdrugs. Cancer Res 1992; 52(1):127-31; Retrievedfrom http://www.ncbi.nlm.nih.gov/pubmed/1727373;PMID:1727373

27. Minami T, Kijima T, Kohmo S, Arase H, Otani Y,Nagatomo I, Kumanogoh A. Overcoming chemoresist-ance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicityand VEGF-targeted antiangiogenesis. Sci Rep 2013;3:2669; PMID:24036898; http://dx.doi.org/10.1038/srep02669

28. Synthon press release of April 02, 2014; http://www.synthon.com/en/Corporate/News/PressReleases/Synthons-Anti-HER2-ADC-Frontrunner-SYD985-Outperforms-Only-Available-HER2-targeting-ADC.aspx

29. https://clinicaltrials.gov/ct2/show/NCT0227771730. Axup JY, Bajjuri KM, Ritland M, Hutchins BM, Kim

CH, Kazane SA, Schultz PG. Synthesis of site-specificantibody-drug conjugates using unnatural amino acids.Proc Natl Acad Sci USA 2012; 109(40):16101-6;PMID:22988081; http://dx.doi.org/10.1073/pnas.1211023109

31. International Patent Application WO2014089127A1,assigned to Merrimack. 12 June 2014; Available athttp://worldwide.espacenet.com/publicationDetails/originalDocument?CCDWO&NRD2014089127A1&KCDA1&FTDD&NDD&dateD20140612&DBD&&localeDen_EP

32. Hu S. Homogeneous ADCs of Herceptin-MMAE withNon-cleavable Linker is more Potent than that with a


http://dx.doi.org/10.1080/19420862.2015.1082019

http://dx.doi.org/10.1080/19420862.2015.1082019

http://cancerres.aacrjournals.org/content/48/12/3330.short

http://cancerres.aacrjournals.org/content/48/12/3330.short

http://www.ncbi.nlm.nih.gov/pubmed/2784353


http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf



https://clinicaltrials.gov/ct2/show/NCT02277717

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=WO&NR=2014089127A1&KC=A1&FT=D&ND=&date=20140612&DB=&&locale=en_EP












Cleavable Linker. Oral presentation at ICA 7th AnnualInternatl Congress on Antibodies; Nanjing, CN; April27, 2015

33. Allen L, Mi Y, Abbas M, Richter W, Hu S. Homoge-neous ADCs bearing two different payloads showstrong synergy in tumor killing. Poster presented atWorld ADC Summit; 2014; San Diego, CA. Availableat http://www.eposters.net/redirect/?IDD2456&UIDD

0&Link=http://www.eposters.net/pdfs/homogeneous-adcs-bearing-two-different-payloads-show-strong-syn-ergy-in-tumor-killing.pdf

34. Grawunder U. Sortase-mediated generation of site-spe-cifically conjugated next-generation ADCs for treat-ment of cancer. Oral Presentation at PEGS conference,Boston, USA, on May 06 2015; 2015.

35. Cohen R, Vugts DJ, Visser GWM, Stigter-van WalsumM, Bolijn M, Spiga M, van Dongen GAMS. Develop-ment of novel ADCs: conjugation of tubulysin ana-logues to trastuzumab monitored by dual radiolabeling.Cancer Res 2014; 74(20):5700-10; PMID:25145670;http://dx.doi.org/10.1158/0008-5472.CAN-14-1141


http://www.eposters.net/redirect/





Documents

Antibody-drug conjugates: Intellectual property considerations · Antibody-drug conjugates: Intellectual property considerations Ulrich Storz* Michalski H€uttermann Patent Attorneys;